This invention relates to pharmaceutically useful compounds, in particular compounds which are useful in the inhibition of cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs), such as type 5 cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDE5). The compounds therefore have utility in a variety of therapeutic areas, including male erectile dysfunction (MED).
Certain cGMP PDE-inhibiting 2-phenyl substituted imidazotriazinone derivatives are disclosed in international patent applications WO 99/24433, WO 99/67244 and WO 01/646777.
According to the present invention, there are provided compounds of general formula I: 
or pharmaceutically or veterinarily acceptable salts, solvates, polymorphs or pro-drugs thereof wherein:
A represents CHOH or Cxe2x95x90O;
X represents O or NR5;
Y represents CH or N;
R1 and R2 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl, C1-C6 alkylaryl, halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10 or SO2R11;
R3, R4 and R5 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R3 and R5 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR2, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
wherein when R1, R2, R3, R4 or R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1, R2, R3, R4 or R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituent groups are optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R6, R7 and R8 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R7 and R8 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR15R16, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R9 and R10 independently represent H, C(O)R6, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R9 and R10 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R11 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R6, R7, R8, R9, R10 or R11 is a C1-C6 alkyl, Het, C1-C6 or C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R12, R13 and R14 independently represent H or C1-C6 alkyl; or R13 and R14 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R15 and R16 independently represent H, C(O)R12, SO2R17 or C1-C6 alkyl or R15 and R16 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R17 represents C1-C6 alkyl;
wherein Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof;
with the proviso that when Y is CH and X is O and A is C(O) then R1, R3 and R4 each do not represent C1-C6 alkyl and R does not represent C1-C6 alkyl or C3-C6 cycloalkyl and
with the further proviso that when Y is CH and X is O and A is CH(OH) then R1 and R3 each do not represent C1-C6 alkyl and R does not represent C1-C6 alkyl or C3-C6 cycloalkyl and R4 is not phenyl or C1-C5 alkyl optionally substituted with up to 2 substituents selected from hydroxy, phenyl, NR9R10 or OC(O)R6 wherein R9 and R10 are H, (C1-C6)alkyl, (C1-C6)alkylphenyl or phenyl groups optionally substituted by hydroxy or OR12 and R6 is (C1-C6)alkyl optionally substituted by halogen or OR12 and wherein OR12 is O(C1-C6)alkyl
which compounds are referred to together hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
The term xe2x80x9carylxe2x80x9d, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl.
The term xe2x80x9cHetxe2x80x9d, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The ring systems may be monocyclic, bicyclic or fused. The term thus includes groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl, imidazopyridinyl and piperazinyl. Substitution at Het may be at a carbon atom of the Het ring or, where appropriate, at one or more of the heteroatoms.
xe2x80x9cHetxe2x80x9d groups may also be in the form of an N-oxide.
Preferred Het groups for use herein are C5-C8 membered ring systems containing at least one N and optionally O, S or mixtures thereof. Highly preferred herein for the Het or alkylHet substitutents on R1 and/or R2 are morpholinyl, piperidinyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl or azetidinyl groups.
The heterocyclic ring that R3 and R5, R7 and R8, R9 and R10, R13 and R14 or R15 and R16 (together with the nitrogen atom to which they are bound) may represent may be any heterocyclic ring that contains at least one nitrogen atom, and which ring forms a stable structure when attached to the remainder of the molecule via the essential nitrogen atom (which, for the avoidance of doubt, is the atom to which R3 and R5, R7 and R8, R9 and R10, R13 and R14 or R15 and R16 are attached respectively). In this respect, heterocyclic rings that R3 and R5, R7 and R8, R9 and R10, R13 and R14 or R15 and R16 (together with the nitrogen atom to which they are bound) may represent include four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain at least one nitrogen atom and optionally contain one or more further heteroatoms selected from nitrogen, oxygen and/or sulfur, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The term thus includes groups such as azetidinyl, pyrrolidinyl, imidazolyl, indolyl, triazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrazolyl and piperazinyl.
The term xe2x80x9cC1-C6 alkylxe2x80x9d (which includes the C1-C6 alkyl part of C1C6 alkylHet and C1-C6 alkylaryl groups), when used herein, includes methyl, ethyl, propyl, butyl, pentyl and hexyl groups. Unless otherwise specified, alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated or be cyclic, acyclic or part cyclic/acyclic. Preferred C1-C6 alkyl groups for use herein are C1-C4 alkyl groups.
Substituted C1-C6 alkylHet and C1-C6 alkylaryl as defined hereinbefore may have substituents on the ring and/or on the alkyl chain.
Halo groups with which the above-mentioned groups may be substituted or terminated include fluoro, chloro, bromo and iodo.
Compounds of general formula I are referred to herein after as xe2x80x9cthe compounds of the inventionxe2x80x9d or xe2x80x9cthe compoundsxe2x80x9d.
A preferred group of compounds according to a further aspect of the invention, are compounds of formula I as hereinbefore defined, wherein:
A represents CHOH or Cxe2x95x90O;
X represents O;
Y represents CH or N;
R1, R2, R3 and R4 independently represent C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl optionally substituted and/or terminated with one or more substituents selected from: halo, OR6, NR9R10, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1, R2, R3 or R4 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituents are optionally substituted and/or terminated with one or more further substituents selected from: halo, OR12 or NR15R16;
wherein R6, R9, R10, R12, R15 and R16 are as hereinbefore defined.
with the proviso that when Y is CH and X is O and A is C(O) then R1, R3 and R4 each do not represent C1-C6 alkyl and R2 does not represent C1-C6 alkyl or C3-C6 cycloalkyl and
with the further proviso that when Y is CH and X is O and A is CH(OH) then R1 and R3 each do not represent C1-C6 alkyl and R2 does not represent C1-C6 alkyl or C3-C6 cycloalkyl and R4 is not phenyl or C1-C5 alkyl optionally substituted with up to 2 substituents selected from hydroxy, phenyl, NR9R10 or OC(O)R6 wherein R9 and R10 are H, (C1-C6)alkyl, (C1-C6)alkylphenyl or phenyl groups optionally substituted by hydroxy or OR12 and R6 is (C1-C6)alkyl optionally substituted by halogen or OR12 and wherein OR12 is O(C1-C6)alkyl.
Highly preferred herein are compounds as defined above wherein Yxe2x95x90CH or N, preferably N and Axe2x95x90C(O) and R1xe2x95x90C1-C4 alkyl or C1-C4 alkylHet, preferably C1-C3 alkylHet and R2 and R4 are independently selected from C1-C4 alkyl, preferably C1-C3 alkyl and R3xe2x95x90C1-C4 alkyl, preferably C2xe2x80x94C4 alkyl wherein the Het group is a morpholinyl, piperidinyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl or azetidinyl group, and is preferably morpholinyl or piperidinyl.
According to another aspect of the present invention there are provided preferred compounds of general formula (I) wherein:
A represents CHOH or Cxe2x95x90O;
X represents O;
Y represents N;
R1, R2, R3 and R4 independently represent C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl optionally substituted and/or terminated with one or more substituents selected from: halo, OR6, NR9R10, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1, R2, R3 or R4 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituents are optionally substituted and/or terminated with one or more further substituents selected from: halo, OR12 or NR15R16;
wherein R6, R9, R10, R12, R15 and R16 are as hereinbefore defined.
According to a yet further aspect the present invention provides alternative preferred compounds of general formula (I) as defined hereinbefore wherein:
A represents Cxe2x95x90O;
X represents O or NR5 and is preferably O;
Y represents CH or N, and is preferably CH;
R1 and R2 independently represent H, Het, C1-C6 alkylHet, aryl, C1-C6 alkylaryl, halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10 or SO2R11;
R3 or R4 independently represent H, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
R5 independently represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R3 and R5 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
wherein when R1, R2, R or R4 is a C1-C6 alkyl, Het, C1-C6alkylHet, aryl or C1-C6 alkylaryl group, such Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1, R2, R3 or R4 is a Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituent groups are optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
wherein when R5 independently represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituent groups are optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R6, R7 and R8 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R7 and R8 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR12; NR15R16, SO2NR15R16 or SO2R17;
R9 and R10 independently represent H, C(O)R6, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R9 and R10 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R11 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R6, R7, R8, R9, R10 or R11 is a C1-C6 alkyl, Het, C1-C6 or C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R12, R13 and R14 independently represent H or C1-C6 alkyl; or R13 and R14 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R15 and R16 independently represent H, C(O)R12, SO2R11 or C1-C6 alkyl or R15 and R16 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R17 represents C1-C6 alkyl;
wherein Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof.
According to an additional aspect the present invention provides alternative preferred compounds of general formula (I) as defined hereinbefore wherein:
A represents CH(OH);
X represents O or NR5 and is preferably O;
Y represents CH or N, and is preferably CH;
R1 and R2 independently represent H, Het, C1-C6 alkylHet, aryl, C1-C6 alkylaryl, halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10 or SO2R11;
R3 represents H, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
R4 represents H, Het or C1-C6 alkylHet;
R5 independently represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R3 and R5 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
wherein when R1, R2 or R3 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group, such Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1, R2 or R3 is a Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituent groups are optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
wherein when R4 is a Het or C1-C6 alkylHet group, such Het or C1-C6 alkylHet group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R4 is a Het or C1-C6 alkylHet group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituent groups are optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
wherein when R5 independently represents H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituent groups are optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R6, R7 and R8 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R7 and R8 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R9 and R10 independently represent H, C(O)R12, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R9 and R10 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R11 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R6, R7, R8, R9, R10 or R11 is a C1-C6 alkyl, Het, C1-C6 or C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17,
R12, R13 and R14 independently represent H or C1-C6 alkyl; or R13 and R14 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R15 and R16 independently represent H, C(O)R12, SO2R17 or C1-C6 alkyl; or R15 and R16 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R17 represents C1-C6 alkyl;
wherein Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof.
According to a yet further aspect the present invention provides compounds of general formula (I): 
or pharmaceutically or veterinarily acceptable salts, solvates, polymorphs or pro-drugs thereof wherein:
A represents CHOH or Cxe2x95x90O;
X represents O or NR5;
Y represents CH or N;
R1 and R2 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl, C1-C6 alkylaryl, halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10 or SO2R11;
R3, R4 and R5 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R3 and R5 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16, SO2R17;
wherein when R1, R2, R3, R4 or R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR6, OC(O)R6, C(O)R6, C(O)OR6, NR6C(O)NR7R8, NR6C(O)OR6, OC(O)NR7R8, C(O)NR9R10, NR9R10, SO2NR9R10, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R1, R2, R3, R4 or R5 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl C1-C6 alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl, such substituent groups are optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R6, R7 and R8 independently represent H, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R7 and R8 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R9 and R10 independently represent H, C(O)R6, SO2R11, C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
or R9 and R10 together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R11 represents C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl;
wherein when R6, R7, R8, R9, R10 or R11 is a C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group, such C1-C6 alkyl, Het, C1-C6 alkylHet, aryl or C1-C6 alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR12, OC(O)R12, C(O)R12, C(O)OR12, NR12C(O)NR13R14, NR12C(O)OR12, OC(O)NR13R14, C(O)NR15R16, NR15R16, SO2NR15R16 or SO2R17;
R12, R13 and R14 independently represent H or C1-C6 alkyl; or R13 and R14 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R15 and R16 independently represent H, C(O)R12, SO2R17 or C1-C6 alkyl; or R15 and R16 together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R17 represents C1-C6 alkyl;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof.
The pharmaceutically or veterinarily acceptable salts of the compounds which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids. Examples include the HCl, HBr, HI, sulphate or bisulphate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccarate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. Compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts. For a review on suitable pharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977.
The pharmaceutically acceptable solvates of the compounds include the hydrates thereof.
Also included within the scope herein are various salts of the compounds and polymorphs thereof.
Where a compound contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. Where a compound contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compound and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
All stereoisomers of the compounds are included within the scope herein.
The compounds may exhibit tautomerism. All tautomeric forms of the compounds, and mixtures thereof, are included within the scope herein.
Also included within the scope of the application are radiolabelled derivatives of the compounds which are suitable for biological studies.
Preparation
According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated below.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention:
1. Compounds of formula I may be prepared by cyclisation of a corresponding compound of formula II: 
wherein R1, R2, R3, R4, X, Y and A are as defined previously for compounds of formula I, for example under conditions known to those skilled in the art. Such conditions include reaction, at between room and reflux temperature, in the presence of a suitable (Lewis acidic) dehydrating agent (e.g. phosphorous oxychloride) and an appropriate solvent (e.g. 1,2-dichloroethane), or as otherwise described in the prior art.
Compounds of formula II may be prepared by the reaction of corresponding compounds of formula III: 
wherein R17 represents C1-C6 alkyl, and R1 and R2 are as defined previously for compounds of formula II, with compounds of formula IV: 
or a suitable acid addition salt thereof (e.g. an hydrogen chloride salt), wherein R3, R4, X, Y and A are as defined previously for compounds of formula II, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at between room and reflux temperature (e.g. 70xc2x0 C.) in the presence of a suitable solvent (e.g. ethanol, diethyl ether, 1,4-dioxane or N,N-dimethylformamide).
Compounds of formula III may be prepared via standard techniques, for example by decarboxylation of corresponding compounds of formula V: 
wherein R1, R2 and R17 are as defined previously for compounds of formula III, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at elevated temperature (e.g. reflux temperature) in the presence of a suitable solvent (e.g. methanol or ethanol) and optionally in the presence of a suitable base (e.g. sodium hydrogencarbonate).
Compounds of formula V may be prepared by the reaction of corresponding compounds of formula VI: 
wherein R1 and R2 are as defined previously for compounds of formula V, with compounds of formula VII: 
wherein R17 is as defined previously for compounds of formula V, and L1 is a leaving group such as halo, preferably chloro, for example under conditions known to those skilled in the art. Such conditions include reaction, at between room and reflux temperature, in the presence of a suitable organic solvent (e.g. THF or ether), an appropriate base (e.g. pyridine, sodium hydride, potassium tert-butoxide, lithium diisopropyl-amide, piperidine or triethylamine) optionally in the presence of a suitable catalyst (e.g. 4-(dimethylamino)pyridine), and optionally with the prior conversion of VI into a 1,3-oxazol-5(4H)-one with excess VII (Dakin-West reaction).
Compounds of formula III may alternatively be prepared by the reaction of corresponding compounds of formula VIII: 
wherein R1, R2 and R17 are as defined previously for compounds of formula III, with ozone in a stream of oxygen, followed by reduction of the resulting ozonide, for example, for both steps, under conditions known to those skilled in the art.
Conditions for the ozonation include, for example, reaction at sub-ambient temperature (e.g. xe2x88x9270xc2x0 C.) in the presence of a suitable solvent (e.g. dichloromethane). Conditions for reduction of the intermediate ozonide include, for example, reaction at sub-ambient temperature (e.g. xe2x88x9270xc2x0 C.) with a suitable reducing agent (e.g. dimethyl sulfide), followed by treatment (at the same temperature) with an appropriate base (e.g. pyridine).
Compounds of formula VIII may be prepared by the reaction of corresponding compounds of formula IX: 
wherein L represents a suitable leaving group (e.g. xe2x80x94N(CH3)OCH3 or chloro) and R1 and R2 are as defined previously for compounds of formula VIII, with a compound of formula X: 
wherein M represents H or a suitable metal-containing moiety (e.g. Na, Li, Mg(II) halide, or a cuprate) and R17 is as defined previously for compounds of formula VIII, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction of a compound of formula IX at between xe2x88x9280xc2x0 C. and room temperature in the presence of a suitable solvent (e.g. THF) with a mixture formed by reacting, at sub-ambient temperature (e.g. xe2x88x9278xc2x0 C.), a compound of formula X in which M represents H (e.g. ethyl vinyl ether), a suitable organolithium reagent (e.g. tert-butyllithium), an appropriate solvent (e.g. THF) and, optionally, a source of a suitable metal salt (e.g. MgBr2 diethyl etherate).
Compounds of formula IX may be prepared from corresponding compounds of formula VI, as hereinbefore defined, under conditions known to those skilled in the art.
Compounds of formula III may alternatively be prepared by reaction of corresponding compounds of formula XI: 
wherein R1, R2 and R17 are as previously defined for compounds of formula III, with an oxidising agent (e.g. Dess-Martin periodinane) at between xe2x88x9278xc2x0 C. and reflux temperature in a suitable solvent (e.g. DCM).
Compounds of formula XI may be prepared by the reaction of compounds of formula XII: 
wherein R1 and R2 are as previously defined for compounds of formula XI, with HCl(g) in R17OH, wherein R17 is as previously defined for compounds of formula XI, at between xe2x88x9210xc2x0 C. and 20xc2x0 C., followed by reaction with aqueous base (e.g. 10% Na2CO3 soln.) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XII may be prepared by the reaction of compounds of formula XIII: 
wherein R1 and R2 are as previously defined for compounds of formula XII, with a source of cyamide (e.g. acetone cyanohydrin) in a suitable solvent (e.g. DCM), optionally in the presence of a base (e.g. Et3N), at between 0xc2x0 C. and reflux temperature.
Compounds of formula XIII may be prepared by the reaction of compounds of formula XIV: 
wherein R1 and R2 are as previously defined for compounds of formula XIII, with a source of hydride (e.g. LiAlH4) in a suitable solvent (e.g. THF) at between about xe2x88x9278xc2x0 C. and 20xc2x0 C.
Compounds of formula XIV may be prepared from compounds of formula VI using conditions known to those skilled in the art.
Compounds of formula IV may be prepared via standard techniques, for example by reaction of corresponding compounds of formula XV: 
or an acid addition salt thereof (e.g. a hydrogen chloride salt), wherein R3, R4, X, Y and A are as defined previously for compounds of formula IV, with hydrazine, for example under conditions known to those skilled in the art. Such conditions include, for example, reaction at between xe2x88x9210xc2x0 C. and room temperature in the presence of a suitable solvent (e.g. a C1-C3 alcohol), or as otherwise described in the prior art.
In a particular embodiment, a compound of formula IV is formed in situ by reaction at low to ambient temperature (e.g. xe2x88x9210 to 25xc2x0 C.) of a compound of formula XV with hydrazine hydrate in an alcoholic solution. This is followed by addition of a compound of formula III, after which the mixture is brought to reflux, eventually yielding a compound of formula II.
Compounds of formula XV may be prepared from corresponding compounds of formula XVI, which in turn may be prepared from compounds of formula XVII, which in turn may be prepared from compounds of formula XVIII using conditions known to those skilled in the art: 
Suitable conditions for the amide transformation of the acid XVIII to the corresponding amide compound XVII and for the subsequent dehydration reaction to prepare the nitrile compound XVI from compound XVII and for the ammonia addition or amidine formation reaction from compound XVI to compound XV will be known to the skilled chemist.
Compounds of formula IV may alternatively be prepared by the reaction of compounds of formula XIX: 
wherein A, Y, X, R3 and R4 are as defined previously for compounds of formula IV, with hydrazine in a suitable solvent (e.g. THF) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XIX may be prepared by the reaction of compounds of formula XX: 
wherein A, X, Y, R3 and R4 are as defined previously for compounds of formula XIX, with a methylating agent (e.g. iodomethane) in a suitable solvent (e.g. acetone) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XX may be prepared by the reaction of compounds of formula XVII with Lawesson""s reagent in a suitable solvent (e.g. toluene) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XVIII, where Y represents CH and A represents Cxe2x95x90O, may be prepared from corresponding compounds of formula XXI: 
wherein X and R3 are as defined previously for compounds of formula XVIII, by using the Friedel-Crafts acylation reaction. Typical conditions are to use ClC(O)R4, wherein R4 is as defined previously for compounds of formula XVIII, (1 to 3 equivalents) and, optionally, a Lewis acid (e.g. 2 to 10 equivalents AlCl3) in an organic solvent (e.g. dichloromethane) at between 0xc2x0 C. and reflux temperature.
Alternatively, compounds of formula XVIII, may be prepared from corresponding compounds of formula XXII: 
wherein R3, X and Y are as defined previously for compounds of formula XVIII, and Hal represents chloro, bromo or iodo, by conversion of Hal to AR4. This can be achieved by any one of the routes outlined below:
(a) so-called xe2x80x9cHeckxe2x80x9d conditions (e.g. 2 equivalents of a source of an acyl anion equivalent (such as butyl vinyl ether), 1.7 equivalents of Et3N and catalytic amounts of Pd(OAc)2 and P(o-tol)3, in MeCN at between room temperature and reflux). Performing a Heck reaction on an alkyl alkenyl ether will give products where A represents Cxe2x95x90O. Such reactions are not suitable when R4 is aryl; or
(b) so-called xe2x80x9cSonogashiraxe2x80x9d conditions (for example as described in Synthesis 1980, 8, 627, such as 1.5 to 5 equivalents of a terminal alkyne and 0.024 to 0.03 equivalents of Pd(PPh3)2Cl2/Cul, in Et3N and MeCN at between room temperature and 60xc2x0 C.), followed by hydrolysis of the resultant alkyne (typical conditions 0.3 equivalents HgSO4, H2SO4, acetone at reflux). Note, this procedure will give products where A represents Cxe2x95x90O. Such reactions are not suitable when R4 is aryl; or
(c) Halogen/lithium exchange followed by quenching onto an acyl chloride (to give products where A represents Cxe2x95x90O). Alternatively, the anion may be quenched onto an aldehyde to give products where A represents CHOH. This alcohol may then be re-oxidised to the corresponding ketone by using standard oxidising agents such as manganese dioxide. Preferred conditions for acyl chloride reaction: 1 to 2 equivalents of n-Butyl Lithium, 1 to 2 equivalents of R4COCl in THF, at from about xe2x88x9278xc2x0 C. to about room temperature. If for example R4COCl is LCH2COCl (where L is a leaving group such as methanesulphonate, p-toluenesulphonate or halo, preferably chloro or bromo), then once the above procedure has been performed the product can be further functionalised by displacement of L with a nucleophile (e.g. primary or secondary amine); or
(d) Formation of Grignard or zincate through addition of magnesium or a zinc source (e.g. zinc, zinc chloride, Reike zinc), followed by quenching onto an acyl chloride (to give products where A represents Cxe2x95x90O). Alternatively the Grignard or zinc reagent may be quenched onto an aldehyde to give products where A represents CHOH. Again, the alcohol formed may be oxidised to give the required ketone as detailed hereinbefore; or
(e) Carbonylation to yield a carboxylic acid, ester, or Weinreb amide. Preferred conditions: CO (50 psi), Pd(OAc)2 (0.03 equivalents), 1,1xe2x80x2-bis(diphenylphosphino)ferrocene (0.045 equivalents), triethylamine (5 equivalents), and suitable nucleophile (e.g. alcohol, amine) at from 40 to about 80xc2x0 C. Alternatively the Weinreb amide may be synthesised from the carboxylic acid and the aldehyde may be synthesised from the ester or carboxylic acid. The acid chloride may be formed from the carboxylic acid. Preferred conditions to from acid chloride from acid: (COCl)2 (1.2 equivalents), N,N-dimethylformamide (drop) in dichloromethane. A nucleophile such as a Grignard reagent or zincate may then be reacted with the ester, Weinreb amide or acid chloride to yield products where A represents Cxe2x95x90O. Alternatively, analogous reactions with the aldehyde would yield products where A represents CHOH. Preferred conditions for addition of Grignard reagent into acid chloride: RMgBr (1 equivalents), Fe(acac)3 (0.03 equivalents) in THF.
Compounds of formula XXII may be prepared by the halogenation of corresponding compounds of formula XXIII: 
wherein X, Y and R3 are as defined previously for compounds of formula XXII, via standard techniques. These include iodinating with N-iodosuccinimide (1 to 2 equivalents) in a 4:1 mixture of trifluoroacetic acid and trifluoroacetic anhydride at between room and reflux temperature (suitable when Y represents N). These standard techniques also include brominating with bromine in DCM at temperatures between room temperature and reflux (suitable when Y represents CH).
2. Compounds of formula I may alternatively be prepared from corresponding compounds of formula XXIV: 
(f) wherein R1, R2, R3, X and Y are as defined previously for compounds of formula I, and Hal represents chloro, bromo or iodo, by conversion of Hal to AR4. This can be by using conditions described hereinbefore for the synthesis of compounds of formula XVIII from compounds of formula XXII.
Compounds of formula XXIV may be prepared by cyclising corresponding compounds of formula XXV: 
wherein R1, R2, R3, X, Y and Hal are as defined previously for compounds of formula XXIV, using conditions described hereinbefore for the synthesis of compounds of formula I from compounds of formula II.
Compounds of formula XXV may be prepared by the reaction of corresponding compounds of formula XXVI: 
wherein R3, X, Y and Hal are as defined previously for compounds of formula XXV, with a compound of formula III, for example using the conditions described hereinbefore for the synthesis of compounds of formula II from compounds of formulae III and IV.
Compounds of formula XXVI may be prepared from corresponding compounds of formula XXVII using the procedure described earlier for the preparation of compounds of formula IV from compounds of formula XV. 
Compounds of formula XXVII may be prepared from corresponding compounds of formula XXVIII, which in turn may be prepared from compounds of formula XXIX, which in turn may be prepared from compounds of formula XXII using conditions known to those skilled in the art: 
Suitable conditions for the amide transformation of compound XXII to compound XXIX and for the dehydration reaction to prepare compound XXVIII from compound XXIX and for the ammonia addition or amidine formation reaction from compound XXVIII to compound XXVII will be known to the skilled chemist.
Compounds of formula XXVI may alternatively be prepared from corresponding compounds of formula XXX: 
wherein Y, X, Hal and R3 are as defined previously for compounds of formula XXVI, with hydrazine in a suitable solvent (e.g. THF) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XXX may be prepared by the reaction of compounds of formula XXXI: 
wherein X, Y, Hal and R3 are as defined previously for compounds of formula XXX, with a methylating agent (e.g. iodomethane) in a suitable solvent (e.g. acetone) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XXXI may be prepared by the reaction of corresponding compounds of formula XXXII: 
wherein X, Y, Hal and R3 are as defined previously for compounds of formula XXXI, with Lawesson""s reagent in a suitable solvent (e.g. toluene) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XXXII may be prepared from corresponding compounds of formula XXII by methods known to those skilled in the art.
3. Compounds of formula I may alternatively be prepared from corresponding compounds of formula XXXIII: 
wherein R1, R2, R3, X and Y are as defined previously for compounds of formula I, by functionalisation alpha to the methyl ketone. This process is not applicable for compounds of formula I where R4 represents aryl or Het. Examples of functionalisation alpha to the methyl ketone include halogenation, preferably bromination, to form alpha-halo ketones; or oxidation to form alpha-hydroxy ketones. These alpha functionalised ketones may be converted into other compounds of formula I using methods known to those skilled in the art (for example, displacement of the halogen by a suitable nucleophile such as a primary or secondary amine; or conversion of the alcohol to an ether using the Mitsunobu reaction). Preferred conditions for bromination are 1.1 equivalents of N-bromosuccinimide and 3 equivalents of triflic acid in dichloromethane.
Alternatively, addition of a base to compounds of formula XXXIII will form the corresponding enolates, which may then be quenched on to a suitable electrophile (e.g. alkyl halide). Typical conditions for this transformation are 1.1 to 2 equivalents of suitable base (e.g. LDA, NaH) and 1.1 to 2 equivalents of suitable electrophile (e.g. alkyl halides) in THF or ether.
Compounds of formula XXXIII may be prepared by the method described for the preparation of compounds of formula I in process 1.
Alternatively compounds of formula XXXIII may be prepared from corresponding compounds of formula XXIV using conditions hereinbefore defined for the preparation of compounds of formula I from compounds of formula XXIV.
4. Compounds of formula I (where Y represents CH) may alternatively be prepared from corresponding compounds of formula XXXIV: 
wherein R1, R2, R3, and X are as defined previously for compounds of formula I, by using the Friedel-Crafts acylation reaction. Typical conditions are to use an acyl chloride (1 to 3 equivalents) and, optionally, a Lewis acid (e.g. 2 to 10 equivalents AlCl3) in an organic solvent (e.g. dichloromethane) at between 0xc2x0 C. and reflux temperature.
Compounds of formula XXXIV may be prepared by the cyclisation of corresponding compounds of formula XXXV: 
wherein R1, R2, R3, and X are as defined previously for compounds of formula XXXIV, using conditions described hereinbefore for the synthesis of compounds of formula I from compounds of formula II.
Compounds of formula XXXV may be prepared by the reaction of corresponding compounds of formula XXXVI: 
wherein R3 and X are as defined previously for compounds of formula XXXV, with a compound of formula III, for example using the conditions described hereinbefore for the synthesis of compounds of formula II from compounds of formulae III and IV.
Compounds of formula XXXVI may be prepared from corresponding compounds of formula XXXVII using the procedure described earlier for the preparation of compounds of formula IV from compounds of formula XV. 
Compounds of formula XXXVII may be prepared from corresponding compounds of formula XXXVIII, which in turn may be prepared from compounds of formula XXXIX, which in turn may be prepared from compounds of formula XXI using conditions known to those skilled in the art: 
Suitable conditions for the amide transformation of compound XXI to compound XXXIX and for the dehydration reaction to prepare compound XXXVIII from compound XXXIX and for the ammonia addition or amidine formation reaction from compound XXXVIII to compound XXXVII will be known to the skilled chemist.
Compounds of formula XXXVI may alternatively be prepared from corresponding compounds of formula XXXX: 
wherein X and R3 are as defined previously for compounds of formula XXXVI, with hydrazine in a suitable solvent (e.g. THF) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XXXX may be prepared by the reaction of compounds of formula XXXXI: 
wherein X and R3 are as defined previously for compounds of formula XXXX, with a methylating agent (e.g. iodomethane) in a suitable solvent (e.g. acetone) at between 20xc2x0 C. and reflux temperature.
Compounds of formula XXXXI may be prepared by the reaction of corresponding compounds of formula XXXIX with Lawesson""s reagent in a suitable solvent (e.g. toluene) at between 20xc2x0 C. and reflux temperature. Compounds of formula XXXIX may be prepared from corresponding compounds of formula XXIII by methods known to those skilled in the art.
Compounds of formulae VI, VII, IX, X, XXI, XXIII and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described hereinbefore, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
When X represents O, R3 can be exchanged for an alternative R3 group (R3a) at any step and in any of the processes described hereinbefore by reacting the appropriate intermediate with R3aOH and a base (e.g. cesium carbonate) at reflux temperature (or, if performed in a sealed vessel, at greater than reflux temperature). Likewise, when X represents O, OR3 can be exchanged for NR3R5 at any step and in any of the processes described hereinbefore by reacting the appropriate intermediate with HNR3R5, optionally in the presence of catalytic copper sulphate, at temperatures between room and reflux temperature (or, if performed in a sealed vessel, at greater than reflux temperature).
Compounds where A represents CHOH can be prepared at any step and in any of the processes described hereinbefore from corresponding compounds where A represents Cxe2x95x90O. This transformation may be achieved by using a suitable reducing agent, preferably sodium borohydride in methanol. Likewise, compounds where A represents Cxe2x95x90O can be prepared at any step and in any of the processes described hereinbefore from corresponding compounds where A represents CHOH. This transformation may be achieved by using a suitable oxidising agent (e.g. manganese dioxide).
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the course of carrying out the processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl). Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art.
Protection/deprotection strategies as appropriate may be employed such as are known in the literature. Suitable protecting groups for use in accordance with the invention can be found in xe2x80x9cProtecting Groupsxe2x80x9d edited by P. J. Kocienski, Thieme, New York, 1994; and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 2nd edition, T. W. Greeene and P. G. M. Wutz, Wiley-Interscience (1991).
Persons skilled in the art will also appreciate that, in order to obtain compounds of formula I in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
Pharmaceutically acceptable acid addition salts of the compounds of formula I that contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt may then be isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula I with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The present invention also includes all suitable isotopic variations of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the formula (I) and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36Cl, respectively. Certain isotopic variations of the compounds of the formula (I) and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of formula (I) and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of formula (I) may act as prodrugs of other compounds of formula (I).
All protected derivatives, and prodrugs, of compounds of formula (I) are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499-538 and in Topics in Chemistry, Chapter 31, pp 306-316 and in xe2x80x9cDesign of Prodrugsxe2x80x9d by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference).
It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as xe2x80x9cpro-moietiesxe2x80x9d, for example as described by H. Bundgaard in xe2x80x9cdesign of Prodrugsxe2x80x9d (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of formula (I).
Preferred prodrugs for compounds of formula (I) include: alcohols, esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulphoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
The present invention additionally comprises the combination of a cGMP PDE5 inhibitor compound as defined herein, wherein said combination can be administered by sequential, simultaneous or joint administration of a compound with:
(1) one or more naturally occurring or synthetic prostaglandins or esters thereof. Suitable prostaglandins for use herein include compounds such as alprostadil, prostaglandin E1, prostaglandin E0, 13, 14-dihydroprostaglandin E1, prostaglandin E2, eprostinol, natural synthetic and semi-synthetic prostaglandins and derivatives thereof including those described in U.S. Pat. No. 6,037,346 issued on Mar. 14, 2000 and incorporated herein by reference, PGE0, PGE1, PGA1, PGB1, PGF1 xcex1, 19-hydroxy PGA1, 19-hydroxy xe2x80x94PGB1, PGE2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE3xcex1, carboprost tromethamine dinoprost, tromethamine, dinoprostone, lipo prost, gemeprost, metenoprost, sulprostune, tiaprost and moxisylate; and/or
(2) one or more xcex1-adrenergic receptor antagonist compounds also known as xcex1-adrenoceptors or xcex1-receptors or xcex1-blockers. Suitable compounds for use herein include: the xcex1-adrenergic receptors as described in PCT application WO99/30697 published on Jun. 14, 1998, the disclosures of which relating to xcex1-adrenergic receptors are incorporated herein by reference and include, selective xcex11-adrenoceptors or xcex12-adrenoceptors and non-selective adrenoceptors, suitable xcex11-adrenoceptors include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine, rauwolfa alkaloids, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, terazosin, abanoquil and prazosin; xcex12-blockers from U.S. Pat. No. 6,037,346 [Mar. 14, 2000] dibenamine, tolazoline, trimazosin and dibenamine; xcex1-adrenergic receptors as described in U.S. Pat. Nos. 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000 each of which is incorporated herein by reference; xcex12-Adrenoceptors include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as pirxamine; and/or
(3) one or more NO-donor (NO-agonist) compounds. Suitable NO-donor compounds for use herein include organic nitrates, such as mono- di or tri-nitrates or organic nitrate esters including glyceryl brinitrate (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3-morpholinosydnonimine molsidomine, S-nitroso-N-acetyl penicilliamine (SNAP) S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso-N-cysteine, diazenium diolates,(NONOates), 1,5-pentanedinitrate, L-arginene, ginseng, zizphi fructus, molsidomine, Re-2047, nitrosylated maxisylyte derivatives such as NMI-678-11 and NMI-937 as described in published PCT application WO 0012075; and/or
(4) one or more potassium channel openers. Suitable potassium channel openers for use herein include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-amini pyridine, BaCl2; and/or
(5) one or more dopaminergic agents, preferably apomorphine or a selective D2, D3 or D2/D3 agonist such as pramipexol and ropirinol (as claimed in WO 0023056), L-Dopa or carbi dopa, PNU 95666 (as claimed in WO 0040226); and/or
(6) one or more vasodilator agents. Suitable vasodilator agents for use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine, halo peridol, Rec 15/2739, trazodone; and/or
(7) one or more thromboxane A2 agonists; and/or
(8) one or more ergot alkoloids; Suitable ergot alkaloids are described in U.S. Pat. No. 6,037,346 issued on Mar. 14, 2000 and include acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride, terguride; and/or
(9) one or more compounds which modulate the action of atrial natruretic factor (also known as atrial naturetic peptide), B and C type naturetic factors such as inhibitors or neutral endopeptidase; and/or
(10) one or more compounds which inhibit angiotensin-converting enzyme such as enapril, and one or more combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat; and/or
(11) one or more angiotensin receptor antagonists such as losartan; and/or
(12) one or more substrates for NO-synthase, such as L-arginine; and/or
(13) one or more calcium channel blockers such as amlodipine; and/or
(14) one or more antagonists of endothelin receptors and inhibitors or endothelin-converting enzyme; and/or
(15) one or more cholesterol lowering agents such as statins (e.g. atorvastatin/Lipitorxe2x80x94trade mark) and fibrates; and/or
(16) one or more antiplatelet and antithrombotic agents, e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activating factor inhibitors; and/or
(17) one or more insulin sensitising agents such as rezulin and hypoglycaemic agents such as glipizide; and/or
(18) one or more COX 2 inhibitors; and/or
(19) pregabalene; and/or
(20) gabapentene; and/or
(21) one or more acetylcholinesterase inhibitors such as donezipil; and/or
(22) one or more steroidal anti-inflammatory agents; and/or
(23) one or more estrogen agonists and/or estrogen antagonists, preferably raloxifene or lasofoxifene, (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof (compound A below) the preparation of which is detailed in WO 96/21656. 
Compound A
(24) one or more one or more of a further PDE inhibitor, more particularly a PDE 2, 4, 7 or 8 inhibitor, preferably PDE2 inhibitor, said inhibitors preferably having an IC50 against the respective enzyme of less than 100 nM: and/or
(25) one or more of an NPY (neuropeptide Y) inhibitor, more particularly NPY1 or NPY5 inhibitor, preferably NPY1 inhibitor, preferably said NPY inhibitors (including NPY Y1 and NPY Y5) having an IC50 of less than 100 nM, more preferably less than 50 nM, suitable NPY and in particular NPY1 inhibitor compounds are described in EP-A-1097718; and/or
(26) one or more of vasoactive intestinal peptide (VIP), VIP mimetic, more particularly mediated by one or more of the VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide), one or more of a VIP receptor agonist or a VIP analogue (eg Ro-125-1553) or a VIP fragment, one or more of a xcex1-adrenoceptor antagonist with VIP combination (eg Invicorp, Aviptadil); and/or
(27) one or more of a melanocortin receptor agonist or modulator or melanocortin enhancer, such as melanotan 11, PT-14, PT-141 or compounds claimed in WO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, WO-09954358; and/or
(28) one or more of a serotonin receptor agonist, antagonist or modulator, more particularly agonists, antagonists or modulators for 5HT1A (including VML 670), 5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-09902159, WO-00002550 and/or WO-00028993; and/or
(29) one or more of a modulator of transporters for noradrenaline, dopamine and/or serotonin, such as bupropion, GW-320659; and/or
(30) one or more of a purinergic receptor agonist and/or modulator; and/or
(31) one or more of a neurokinin (NK) receptor antagonist, including those described in WO-09964008; and/or
(32) one or more of an opioid receptor agonist, antagonist or modulator, preferably agonists for the ORL-1 receptor; and/or
(33) one or more of an agonist or modulator for oxytocin/vasopressin receptors, preferably a selective oxytocin agonist or modulator; and/or
(34) one or more modulators of cannabinoid receptors; and/or
(35) one or more of an NEP inhibitor, preferably wherein said NEP is EC 3.4.24.11 and more preferably wherein said NEP inhibitor is a selective inhibitor for EC 3.4.24.11, more preferably a selective NEP inhibitor is a selective inhibitor for EC 3.4.24.11, which has an IC50 of less than 100 nM (e.g. ompatrilat, sampatrilat) suitable NEP inhibitor compounds are described in EP-A-1097719; and/or
(36) one or more compounds which inhibit angiotensin-converting enzyme such as enalapril, and one or more combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase such as omapatrilat; and/or
(37) one or more tricyclic antidepressants, e.g. amitriptiline; and/or
(38) one or more non-steroidal anti-inflammatory agents; and/or
(39) one or more angiotensin-converting enzyme (ACE) inhibitors, e.g. quinapril; and/or
(40) one or more anti-depressants (such as clomipramine and SSRIs (such as paroxetine and sertaline).
wherein said combination can be in the form of co-administration, simultaneous administration, concurrent administration, or stepwise administration.
Medical Use
The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals, including humans. They are therefore indicated as pharmaceuticals, as well as for use as animal medicaments.
According to a further aspect of the invention there is provided the compounds of the invention for use as pharmaceuticals, and for use as animal medicaments.
In particular, compounds of the invention have been found to be potent and selective inhibitors of cGMP PDEs, such as cGMP PDE5, for example as demonstrated in the tests described below, and are thus useful in the treatment of medical conditions in humans, and in animals, in which cGMP PDEs, such as cGMP PDE5, are indicated, and in which inhibition of cGMP PDEs, such as cGMP PDE5, is desirable.
By the term xe2x80x9ctreatmentxe2x80x9d, we include both therapeutic (curative), palliative or prophylactic treatment.
Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a medical condition in which a cGMP PDE (e.g. cGMP PDE5) is indicated. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a medical condition in which inhibition of a cGMP PDE (e.g. cGMP PDE5) is desirable.
The compounds of the invention are thus expected to be useful for the curative, palliative or prophylactic treatment of mammalian sexual disorders. In particular, the compounds are of value in the treatment of mammalian sexual dysfunctions such as male erectile dysfunction (MED), impotence, female sexual dysfunction (FSD), (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder or female sexual orgasmic dysfunction (FSOD) as well as sexual dysfunction due to spinal cord injury or selective serotonin re-uptake inhibitor (SSRI) induced sexual dysfunction but, clearly, will be useful also for treating other medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated. Such conditions include premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, diseases and conditions of the eye such as glaucoma, optic neuropathy, macular degeneration, elevated intra-occular pressure, retinal or arterial occulsion and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
Further medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated, and for which treatment with compounds of the present invention may be useful, include pre-eclampsia, Kawasaki""s syndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy, neuropathy including autonomic and peripheral neuropathy and in particular diabetic neuropathy and symptoms thereof (e.g. gastroparesis), peripheral diabetic neuropathy, Alzheimer""s disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure, haemorrhoids, hypoxic vasoconstriction, hypoxic vasoconstriction, diabetes, type 2 diabetes mellitus, the insulin resistance syndrome, insulin resistance, impaired glucose tolerance, as well as the stabilisation of blood pressure during haemodialysis.
Particularly preferred conditions include MED and FSD.
Thus, the invention provides a method of treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated, in an animal (e.g. a mammal, including a human being), which comprises administering a therapeutically effective amount of a compound of the invention to a mammal in need of such treatment.
Pharmaceutical Preparations
The compounds will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.
The compounds may also be combined with any other drugs useful in the inhibition of cGMP-PDEs, such as cGMP-PDE5.
The compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity can be administered alone but, in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds or salts or solvates thereof can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications. The compounds may also be administered via intracavernosal injection. The compounds may also be administered via fast dispersing or fast dissolving dosages forms.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device. Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. Release rate modifying excipients maybe present both within the dosage form i.e. within the matrix, and/or on the dosage form i.e. upon the surface or coating.
Fast dispersing or dissolving dosage formulations (FDDFs) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
The compounds can also be administered parenterally, for example, intracavernosally, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. For such parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of the compounds or salts or solvates thereof will usually be from 10 to 500 mg (in single or divided doses).
Thus, for example, tablets or capsules of the compounds or salts or solvates thereof may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The skilled person will also appreciate that, in the treatment of certain conditions (including MED and FSD), compounds may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
Example Tablet Formulation
In general a tablet formulation could typically contain between about 0.01 mg and 500 mg of the compound (or a salt thereof) whilst tablet fill weights may range from 50 mg to 1000 mg. An example formulation for a 10 mg tablet is illustrated:
Such tablets can be manufactured by standard processes, for example, direct compression or a wet or dry granulation process. The tablet cores may be coated with appropriate overcoats.
The compounds can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark] or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 1 to 50 mg of the compound for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
The compounds may also be formulated for delivery via an atomiser. Formulations for atomiser devices may contain the following ingredients as solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.
Alternatively, the compounds or salts or solvates thereof can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds or salts or solvates thereof may also be dermally administered. The compounds or salts or solvates thereof may also be transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal routes.
For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds or salts or solvates thereof can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
Generally, in humans, oral administration of the compounds is the preferred route, being the most convenient and, for example in MED, avoiding the well-known disadvantages associated with intracavernosal (i.c.) administration. A preferred oral dosing regimen in MED for a typical man is from 25 to 250 mg of compound when required. In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, sublingually or buccally.
For veterinary use, the compound, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or pro-drug thereof, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
Thus, according to a further aspect there is provided a pharmaceutical formulation including a compound as detailed hereinbefore in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.
In addition to the fact that the compounds inhibit cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs) and in particular, are potent and selective inhibitors of cGMP PDE5, the compounds may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
The biological activities of the compounds were determined by the following test methods.
Phosphodiesterase (PDE) Inhibitory Activity
Compounds of the present invention are potent and selective cGMP PDE5 inhibitors. In vitro PDE inhibitory activities against cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) and cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) phosphodiesterases were determined by measurement of their IC50 values (the concentration of compound required for 50% inhibition of enzyme activity).
The required PDE enzymes were isolated from a variety of sources, including human corpus cavernosum, human platelets, human cardiac ventricle, human skeletal muscle and human and canine retina, essentially by the method of W. J. Thompson and M. M. Appleman (Biochem., 1971, 10, 311). In particular, the cGMP-specific PDE (PDE5) and the cGMP-inhibited cAMP PDE (PDE3) were obtained from human corpus cavernosum tissue or human platelets; the cGMP-stimulated PDE (PDE2) was obtained from human corpus cavernosum or human platelets; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1) from human cardiac ventricle; the cAMP-specific PDE (PDE4) from recombinant clone or human skeletal muscle; and the photoreceptor PDE (PDE6) from canine or human retina. Phosphodiesterases 7-11 were generated from full length human recombinant clones transfected into SF9 cells.
Assays were performed either using a modification of the xe2x80x9cbatchxe2x80x9d method of W. J. Thompson et al. (Biochem., 1979, 18, 5228) or using a scintillation proximity assay for the direct detection of AMP/GMP using a modification of the protocol described by Amersham plc under product code TRKQ7090/7100. In summary, the effect of PDE inhibitors was investigated by assaying a fixed amount of enzyme in the presence of varying inhibitor concentrations and low substrate, (cGMP or cAMP in a 3:1 ratio unlabelled to [3H]-labeled at a conc xcx9cxc2xd Km) such that IC50≅Ki. The final assay volume was made up to 102 xcexcl with assay buffer [20 mM Tris-HCl pH 7.4, 5 mM MgCl2, 1 mg/ml bovine serum albumin]. Reactions were initiated with enzyme, incubated for 30-60 min at 30xc2x0 C. to give  less than 30% substrate turnover and terminated with 50 xcexcl yttrium silicate SPA beads (containing 3 mM of the respective unlabelled cyclic nucleotide for PDEs 3, 9 and 11). Plates were re-sealed and shaken for 20 min, after which the beads were allowed to settle for 30 min in the dark and then counted on a TopCount plate reader (Packard, Meriden, Conn.). Radioactivity units were converted to % activity of an uninhibited control (100%), plotted against inhibitor concentration and inhibitor IC50 values obtained using the xe2x80x98Fit Curvexe2x80x99 Microsoft Excel extension or in-house equivalent. Results from these tests show that the compounds of the present invention are potent and selective inhibitors of cGMP-specific PDE5.
In vitro Metabolism
In vitro metabolism experiments were carried out in the hepatic microsomal fractions from man. Transplant-quality human liver tissue was obtained from the International Institute for the Advancement of Medicine (Exton, Pa., USA). Microsomes were prepared according to the method described in Biochemical Pharmacology, 1966, 48, 2147-2156 and stored at xe2x88x9280xc2x0 C. The concentrations of protein and cytochrome P450 were determined by standard methods described in Journal of Biological Chemistry, 1951, 193, 265-275 and Journal of Biological Chemistry, 1964, 239, 2370-2378.
Microsomal incubations (1.5 ml) were prepared containing 0.5 xcexcM cytochrome P450, 200 mM phosphate buffer (pH 7.4), 0.1 M MgCl2, 0.1 M isocitric acid, 1 unit/ml isocitrate dehydrogenase and 20 mM xcex2-NADP. Compounds under study were added after a 5 min preincubation at 37xc2x0 C. to give an initial substrate concentration of 1 xcexcM. The mixture was incubated at 37xc2x0 C. and samples (100 xcexcl) were removed for analysis for up to 60 min. Metabolism in samples was terminated by the addition of NaOH (0.1 M) containing an internal standard (chosen to have similar physicochemical properties to compounds under study), followed by extraction into ethyl acetate (2 ml). The extracts were evaporated to dryness and analysed by LC-MS/MS (Hewlett Packard HP1100 binary pump, Hypersil HS100 C18, 5 cm by 4.6 mm internal diameter, 5 xcexcm column using a mobile phase of 2 mM ammonium acetate in 90:10 methanol/water, aqueous portion adjusted to pH 4 with glacial acetic acid, and a flowrate of 1 ml/min). The mass spectrometer was a Sciex API 2000 with TurbolonSpray interface using a positive ion multiple reaction monitoring (MRM) detection mode. Nitrogen was used as curtain, nebuliser, TurbolonSpray and collision gases, and the TurbolonSpray temperature was 100xc2x0 C. Typical voltages were as follows: IS=5.2 kV; RNG=380 V; Q0=xe2x88x9210 V; IQ1=xe2x88x9211 V; ST=xe2x88x92151RO1=xe2x88x9211 V; MU=gain adjusted as per Sciex user manual. Collision energy was 55 eV for high MRM, OR=65 V. Dwell time was 200 msec with a 50 msec pause. Data was acquired using MSExpress v 1.1 and processed using Macquan 1.5 (PE Sciex)). Disappearance rate constants (k) in human microsomal preparations were determined by linear regression of the log ratio (compound under study/internal standard) versus time. The in vitro human microsomal half-lives were determined according to the equation t1/2=In 2/k. Results from these studies show that the compounds of the present invention demonstrate desirable human liver microsome (HLM) half-lives.
Those skilled in the art will recognise that an increase in HLM half-life is predictive of reduced clearance in man for compounds cleared predominantly by cytochrome P450 mediated metabolism.
A particular advantage of compounds of the invention, such as for example the compound of Example 1, is desirable in vitro microsomal half-lives. Particularly preferred compounds herein have 2-fold preferably 4-fold and more preferably 5-fold improvements versus compound of the art. Such improved in vitro microsomal half-lives are indicative of reduced clearance in vivo.
Preferred compounds of formula (I) herein have IC50 values of less than about 10 nM for the PDE5 enzyme. A more preferred group of compounds have IC50 values of less than about 5 nM for the PDE5 enzyme. Highly preferred herein are compounds which have IC50 values of less than about 3 nM for the PDE5 enzyme.
In addition, preferred compounds of formula (I) herein have greater than 5-fold selectivity for the PDE5 enzyme versus the PDE6 enzyme. Highly preferred herein are compounds having greater than 10-fold selectivity for the PDE5 enzyme versus the PDE6 enzyme. More preferable herein are compounds having greater than 20-fold selectivity for the PDE5 enzyme versus the PDE6 enzyme and especially preferred are compounds having greater than 30-fold selectivity for the PDE5 enzyme versus the PDE6 enzyme.
Especially preferred herein are compounds which have an IC50 value of less than about 10, more preferably less than about 5 nM and especially less than about 3 nM for the PDE5 enzyme in combination with greater than 10-fold, preferably greater than about 20-fold and especially greater than 30-fold selectivity for the PDE5 enzyme versus the PDE6 enzyme.
As detailed hereinbefore preferred compounds herein have desirable human liver microsome (HLM) half-lives. Especially preferred herein are compounds having HLM half-lives of greater than about 20 minutes, more preferably greater than 60 minutes, and most preferably greater than 120 minutes. Such HLM values can be measured according to the methods detailed hereinbefore.
Thus an especially preferred group of compounds herein have an IC50 value of less than about 10, more preferably less than about 5 nM and especially less than about 3 nM for the PDE5 enzyme in combination with greater than 10-fold, preferably greater than about 20-fold and especially greater than 30-fold selectivity for the PDE5 enzyme versus the PDE6 enzyme and HLM half-lives of greater than about 20 minutes.
Functional Activity
This can be assessed in vitro by determining the capacity of a compound of the invention to enhance sodium nitroprusside-induced relaxation of pre-contracted rabbit corpus cavernosum tissue strips, as described by S. A. Ballard et al. (Brit. J. Pharmacol., 1996,118 (suppl.), abstract 153P).
In vivo Activity
In vivo activity can be tested by screening test compounds in anaesthetised dogs to determine their capacity, after i.v. administration, to enhance the pressure rises in the corpora cavernosa of the penis induced by intracavernosal injection of sodium nitroprusside, using a method based on that described by Trigo-Rocha et al. (Neurourol. and Urodyn., 1994, 13, 71).
Safety Profile
The compounds may be tested at varying i.v and p.o. doses in animals such as mouse and dog, observing for any untoward effects.